CN104496881B - A kind of preparation method of mantoquita catalysis amides compound synthesizing indoline - Google Patents
A kind of preparation method of mantoquita catalysis amides compound synthesizing indoline Download PDFInfo
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- CN104496881B CN104496881B CN201410820260.3A CN201410820260A CN104496881B CN 104496881 B CN104496881 B CN 104496881B CN 201410820260 A CN201410820260 A CN 201410820260A CN 104496881 B CN104496881 B CN 104496881B
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- -1 amides compound Chemical class 0.000 title claims abstract description 27
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title claims description 33
- 238000006555 catalytic reaction Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 89
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 150000002978 peroxides Chemical class 0.000 claims abstract description 5
- 150000001408 amides Chemical class 0.000 claims description 33
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 32
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 20
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical group Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims description 12
- NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 claims description 10
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 10
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 9
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims 2
- 230000000996 additive effect Effects 0.000 claims 2
- 230000005784 autoimmunity Effects 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- 208000011580 syndromic disease Diseases 0.000 claims 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical class CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims 1
- KRDXTHSSNCTAGY-UHFFFAOYSA-N 2-cyclohexylpyrrolidine Chemical compound C1CCNC1C1CCCCC1 KRDXTHSSNCTAGY-UHFFFAOYSA-N 0.000 claims 1
- 229910006069 SO3H Inorganic materials 0.000 claims 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 235000011150 stannous chloride Nutrition 0.000 claims 1
- 239000001119 stannous chloride Substances 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 150000002476 indolines Chemical class 0.000 abstract description 9
- 150000001879 copper Chemical class 0.000 abstract description 8
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 238000007036 catalytic synthesis reaction Methods 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 abstract 1
- 239000002798 polar solvent Substances 0.000 abstract 1
- 238000010992 reflux Methods 0.000 abstract 1
- 239000000758 substrate Substances 0.000 abstract 1
- 238000004440 column chromatography Methods 0.000 description 29
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 28
- 238000000926 separation method Methods 0.000 description 26
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 9
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 9
- 229940045803 cuprous chloride Drugs 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- KILYGFICLVHKJG-UHFFFAOYSA-N CC=1NC=CN1.[N] Chemical compound CC=1NC=CN1.[N] KILYGFICLVHKJG-UHFFFAOYSA-N 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- OSOUNOBYRMOXQQ-UHFFFAOYSA-N 1-chloro-3-methylbenzene Chemical compound CC1=CC=CC(Cl)=C1 OSOUNOBYRMOXQQ-UHFFFAOYSA-N 0.000 description 2
- BIISIZOQPWZPPS-UHFFFAOYSA-N 2-tert-butylperoxypropan-2-ylbenzene Chemical compound CC(C)(C)OOC(C)(C)C1=CC=CC=C1 BIISIZOQPWZPPS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- PHCDUJPIUFPCKN-UHFFFAOYSA-N 2-(2,3-dihydroindol-1-yl)acetaldehyde Chemical compound C1=CC=C2N(CC=O)CCC2=C1 PHCDUJPIUFPCKN-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- UJGLGHFVENLPLA-UHFFFAOYSA-N 2-(nitromethyl)-1h-imidazole Chemical compound [O-][N+](=O)CC1=NC=CN1 UJGLGHFVENLPLA-UHFFFAOYSA-N 0.000 description 1
- VQAUZVOMRVFVKZ-UHFFFAOYSA-N 3,3-dimethyl-2h-indole-1-carbaldehyde Chemical compound C1=CC=C2C(C)(C)CN(C=O)C2=C1 VQAUZVOMRVFVKZ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明提供了一种催化合成吲哚啉的催化合成方法。该方法以易制备得到的酰胺类化合物为原料，以铜盐为催化剂，加入适当配体，以过氧化物为氧化剂，极性溶剂中，在80‑160℃下回流反应得到对应的吲哚啉化合物。反应以铜盐作催化剂，成本较低，毒性较小，贴近绿色环境友好型的理念，且对复杂的底物也能具有较好的催化效果，极大丰富了产物的多样性，该方法的主要优点还有有：实验简便，产率高，适用性广，此法无需加碱也可反应，真正意义上实现高效，经济，低毒的愿景，实用性较强。
The invention provides a catalytic synthesis method for catalytically synthesizing indoline. The method uses easily prepared amide compounds as raw materials, copper salts as catalysts, adding appropriate ligands, peroxides as oxidants, and reflux reaction at 80‑160 °C in polar solvents to obtain the corresponding indolines. compound. The reaction uses copper salt as a catalyst, which has low cost and low toxicity, and is close to the concept of green and environment-friendly, and can also have a good catalytic effect on complex substrates, which greatly enriches the diversity of products. The main advantages are: simple experiment, high yield, wide applicability, this method can react without adding alkali, realize the vision of high efficiency, economy, and low toxicity in a real sense, and has strong practicability.
Description
【技术领域】【Technical field】
本发明属于过渡金属催化有机合成领域，具体地说涉及铜盐作为催化剂，以廉价、低毒的铜盐作催化剂，以酰胺化合物类化合物为原料，以过氧化物为氧化剂，加入配体，在有机溶剂中发生自身偶联关环反应，高产率地得到吲哚啉类衍生物的催化合成方法。The invention belongs to the field of transition metal catalyzed organic synthesis, and specifically relates to copper salts as catalysts, using cheap and low-toxic copper salts as catalysts, using amide compounds as raw materials, using peroxides as oxidants, adding ligands, and A self-coupling ring-closing reaction occurs in an organic solvent, and a catalytic synthesis method for obtaining indoline derivatives with high yield.
【背景技术】【Background technique】
铜催化偶联以其高效、经济、低毒等优势引备受人们关注。特别是近十年来，由于各种催化条件的改进(特别是各类有效配体的开发)，使得铜催化偶联反应得到了迅速发展。随着铜催化研究的深入，利用铜催化偶联参与的串联反应构建各类杂环，成为了化学工作者研究铜盐的一个重要方向。其中铜催化制备含氮有机化合物是有机化学研究中的研究热点和难点。Copper-catalyzed coupling has attracted much attention due to its advantages of high efficiency, economy, and low toxicity. Especially in the past ten years, due to the improvement of various catalytic conditions (especially the development of various effective ligands), copper-catalyzed coupling reactions have been developed rapidly. With the in-depth study of copper catalysis, the construction of various heterocycles by using copper-catalyzed coupling in series reactions has become an important direction for chemists to study copper salts. Among them, copper-catalyzed preparation of nitrogen-containing organic compounds is a research hotspot and difficulty in organic chemistry research.
由于含氮杂环化合物是具有重要生物活性分子，是一些药物的重要组成单元，其中苯并含氮杂化合物大多含有生物活性，普遍存在于药物当中。因此，对于苯并含氮杂环化合物的研究更是备受瞩目，特别是吲哚啉类衍生物。传统合成吲哚啉类衍生物的方法一般是通过把具有取代基的吲哚衍生物还原成对应的吲哚啉衍生物，该法需要加氢还原、硼氢化物还原、金属-酸还原等。然而加氢还原的方法要求高温高压，对反应装置要求高，易产生副产物；硼氢化物的还原法，还原剂价格较贵，成本较高，难以实现工业生产；金属-酸还原体系会产生大量的废酸水，还使用到了汞，具有较大的毒性，对环境会产生污染。因而，继续急需开发便利，高效地合成方法。Since nitrogen-containing heterocyclic compounds are important biologically active molecules and are important constituent units of some drugs, most of the benzo nitrogen-containing heterocyclic compounds contain biological activity and are commonly found in drugs. Therefore, the research on benzo nitrogen-containing heterocyclic compounds has attracted much attention, especially indoline derivatives. The traditional method of synthesizing indoline derivatives is generally by reducing indole derivatives with substituents to corresponding indoline derivatives. This method requires hydrogenation reduction, borohydride reduction, metal-acid reduction, etc. However, the method of hydrogenation reduction requires high temperature and high pressure, high requirements on the reaction device, and easily produces by-products; the reduction method of borohydride, the reducing agent is more expensive, the cost is higher, and it is difficult to realize industrial production; the metal-acid reduction system will produce Mercury is also used in a large amount of waste acid water, which is highly toxic and pollutes the environment. Thus, there continues to be an urgent need to develop convenient and efficient synthetic methods.
近年来，随着过渡金属碳氢活化研究的不断深入，将这一研究理念运用到对吲哚啉衍生物的合成能够弥补还原法的不足，且能实现便捷、高效，经济的愿景。基于此，我们设计了以酰胺化合物为原料，在铜盐催化下，合成了一系列的吲哚啉衍生物，此法无需特殊设备，产率较高，且对环境友好。In recent years, with the continuous deepening of the research on the activation of transition metal hydrocarbons, applying this research concept to the synthesis of indoline derivatives can make up for the shortcomings of the reduction method, and can realize the vision of convenience, efficiency and economy. Based on this, we designed and synthesized a series of indoline derivatives using amide compounds as raw materials under the catalysis of copper salts. This method does not require special equipment, has high yields, and is environmentally friendly.
【发明内容】【Content of invention】
本发明的目的在于提供一种吲哚啉衍生物的绿色催化合成方法。铜盐作催化剂，酰胺类化合物II反应原料，过氧化物为氧化剂，加入适当的配体，得到吲哚啉化合物I。由于此催化体系具有成本较低，催化活性高，操作简单，毒性小，易处理等优点，对于工业化的实现有一定的可行性。The object of the present invention is to provide a green catalytic synthesis method of indoline derivatives. Copper salt is used as catalyst, amide compound II is used as raw material for reaction, peroxide is used as oxidizing agent, and appropriate ligand is added to obtain indoline compound I. Since this catalytic system has the advantages of low cost, high catalytic activity, simple operation, low toxicity, and easy handling, it has certain feasibility for the realization of industrialization.
为达到上述发明目的，本发明提出以下的技术方案：In order to achieve the above-mentioned purpose of the invention, the present invention proposes the following technical solutions:
上述合成方法中，所述酰胺类化合物II和吲哚啉化合物I，其结构式I和II如下：In the above synthetic method, the structural formulas I and II of the amide compound II and the indoline compound I are as follows:
其中，其中R1为苯环上3,4,5,6位上的一取代或二取代H、Br、Cl、I、SO3H、C(CH3)3、CH3、OCH3、吡啶基、Ph、环己基、4-H3COC6H4、C6H5S中的一种，其中二取代基团可相同也可不同；当X为C时，R2为H、CH3、CH2CH2CH3、CH2CH2Cl、OCH3、OC(CH3)3、C(CH3)3、苄基、吡啶基、环己基、Ph、噻吩基、CH2CH-Ph、2,6-di-F-C6H3、2-CF3-C6H4、2-CH3-C6H4、2,6-di-CH3-C6H3、2,6-di-CH3O-C6H3、CH＝CH2、2-CH3O-C6H4、CHCHCH3的一种；当X为S＝O时，R2为4-NO2-C6H4、4-CH3O-C6H4的一种；R3和R4可为相同或不同的CH3、CH2OAc、CH2OCH3、CH2SPh、CH＝CHCH3、Ph、Cy、CH2CH3、Bn中的一种。Among them, where R 1 is monosubstituted or disubstituted H, Br, Cl, I, SO 3 H, C(CH 3 ) 3 , CH 3 , OCH 3 , pyridine at the 3,4,5,6 positions on the benzene ring One of base, Ph, cyclohexyl, 4-H 3 COC 6 H 4 , C 6 H 5 S, where the two substituent groups can be the same or different; when X is C, R 2 is H, CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 Cl, OCH 3 , OC(CH 3 ) 3 , C(CH 3 ) 3 , Benzyl, Pyridyl, Cyclohexyl, Ph, Thienyl, CH 2 CH-Ph , 2,6-di-FC 6 H 3 , 2-CF 3 -C 6 H 4 , 2-CH 3 -C 6 H 4 , 2,6-di-CH 3 -C 6 H 3 , 2,6- One of di-CH 3 OC 6 H 3 , CH=CH 2 , 2-CH 3 OC 6 H 4 , CHCHCH 3 ; when X is S=O, R 2 is 4-NO 2 -C 6 H 4 , One of 4-CH 3 OC 6 H 4 ; R 3 and R 4 can be the same or different CH 3 , CH 2 OAc, CH 2 OCH 3 , CH 2 SPh, CH=CHCH 3 , Ph, Cy, CH 2 One of CH 3 and Bn.
上述合成方法中，催化剂为碘化亚铜，溴化亚铜，氯化铜，氯化亚铜的一种；以酰胺化合物II为1个当量计，下述试剂用量也以此为标准，所述催化剂的用量为0.1-3当量；所述有机溶剂为DMSO、DMF、乙腈、甲苯、对氯甲苯、均三甲苯的一种；所述配体为氮甲基咪唑，2-氨基吡啶，2-吡咯甲酸，苯并三氮唑，4-甲基咪唑，三苯基膦，吡啶中的一种，其中配体的摩尔添加量为1-3当量；所述氧化剂为过氧化氢，过氧化氢叔丁基，过氧化二叔丁基，过氧化叔丁基异丙苯的一种，氧化剂的摩尔添加量为0.1-10当量；所述催化反应的条件为：在80-160℃下反应4-40小时。In the above-mentioned synthetic method, catalyzer is cuprous iodide, cuprous bromide, cupric chloride, a kind of of cuprous chloride; Take amide compound II as 1 equivalent meter, following reagent consumption is also with this as standard, so The consumption of described catalyst is 0.1-3 equivalent; Described organic solvent is a kind of of DMSO, DMF, acetonitrile, toluene, p-chlorotoluene, mesitylene; Described ligand is nitrogen methyl imidazole, 2-aminopyridine, 2 -one of pyrrole carboxylic acid, benzotriazole, 4-methylimidazole, triphenylphosphine, and pyridine, wherein the molar amount of ligand added is 1-3 equivalents; the oxidizing agent is hydrogen peroxide, peroxide Hydrogen tert-butyl, di-tert-butyl peroxide, a kind of tert-butyl cumene peroxide, the molar addition amount of oxidant is 0.1-10 equivalent; the conditions of the catalytic reaction are: react 4- 40 hours.
本发明所提供的一种合成吲哚啉衍生物的高效催化合成方法，开辟了新的经济“绿色”途径，其优点在于：作为原料的酰胺类化合物较多，目标产物的选择性和产率均较高，实验操作简单，同时催化活性高，毒性小，易处理。A high-efficiency catalytic synthesis method for synthesizing indoline derivatives provided by the present invention has opened up a new economic "green" approach, and its advantages are: there are more amide compounds as raw materials, and the selectivity and yield of the target product All are high, the experimental operation is simple, and at the same time, the catalytic activity is high, the toxicity is small, and it is easy to handle.
【附图说明】【Description of drawings】
图1所示是本发明提供的合成吲哚啉化合物的路径图。Shown in Fig. 1 is the route diagram of the synthetic indoline compound provided by the present invention.
【具体实施方式】【Detailed ways】
本发明所提供铜盐催化合成吲哚啉的合成路线，请参见附图1:将原料酰胺、配体、氧化剂和催化剂加入反应容器内，加入溶剂，不需N2保护，在80-160℃的环境下反应4-40h,经柱层析分离得到目标化合物。The synthesis route of indoline catalyzed by copper salt provided by the present invention, please refer to accompanying drawing 1: add raw material amide, ligand, oxidizing agent and catalyst in reaction container, add solvent, do not need N Protection, at 80-160 ℃ Under the environment of reacting for 4-40h, the target compound was separated by column chromatography.
下面结合具体的制备例对本发明做进一步说明：下面结合具体的制备例对本发明做进一步说明：The present invention will be further described below in conjunction with specific preparation examples: The present invention will be further described below in conjunction with specific preparation examples:
制备例1Preparation Example 1
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝H,R3、R4＝CH3)，加入溴化亚铜(0.25eq)，氮甲基咪唑(3eq),滴加过氧化二叔丁基(1eq),滴加DMF 2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3,3-二甲基吲哚啉-1-甲醛，产率为91％。Add amide compound II (X=C, R 1 =H, R 2 =H, R 3 , R 4 =CH 3 ) into a 10mL reaction tube, add cuprous bromide (0.25eq), nitrogen methyl imidazole ( 3eq), di-tert-butyl peroxide (1eq) was added dropwise, DMF 2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3,3-dimethylindoline-1-carbaldehyde was obtained by column chromatography separation with a yield of 91%.
制备例2Preparation example 2
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝CH3,R3＝CH2OAc,R4＝CH3)，加入氯化亚铜(1eq)，氮甲基咪唑(2eq),滴加过氧化氢(3eq),滴加乙腈2mL，反应在140℃下进行12h。反应结束后，经柱层析分离得到3-甲基-3-乙酸甲酯基吲哚啉-1-乙酮，产率为93％。Add amide compound II (X=C, R 1 =H, R 2 =CH 3 , R 3 =CH 2 OAc, R 4 =CH 3 ) into a 10mL reaction tube, add cuprous chloride (1eq), nitrogen Methylimidazole (2eq), hydrogen peroxide (3eq) was added dropwise, acetonitrile 2mL was added dropwise, and the reaction was carried out at 140°C for 12h. After the reaction was completed, 3-methyl-3-acetate methylindoline-1-ethanone was obtained by separation by column chromatography with a yield of 93%.
制备例3Preparation example 3
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝CH3,R3、R4＝Cy)，加入氯化亚铜(0.25eq)，2-氨基吡啶(1eq),滴加过氧化氢(2eq),滴加对氯甲苯2mL，反应在130℃下进行24h。反应结束后，经柱层析分离得到3,3-二环己基吲哚啉-1-乙酮，产率为89％。Add amide compound II (X=C, R 1 =H, R 2 =CH 3 , R 3 , R 4 =Cy) into a 10mL reaction tube, add cuprous chloride (0.25eq), 2-aminopyridine ( 1eq), hydrogen peroxide (2eq) was added dropwise, p-chlorotoluene 2mL was added dropwise, and the reaction was carried out at 130°C for 24h. After the reaction was completed, 3,3-dicyclohexylindoline-1-ethanone was obtained by column chromatography separation with a yield of 89%.
制备例4Preparation Example 4
在10mL反应管中加入酰胺类化合物II(X＝S＝O,R1＝H,R2＝4-O2NC6H4,R3＝CH2SPh,R4＝CH3)，加入溴化亚铜(3eq)，2-氨基吡啶(3eq),滴加过氧化氢(3eq),滴加DMF2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3-甲基-3-苯硫甲醚基-1-4’-硝基苯磺酰基吲哚啉，产率为91％。Add amide compound II (X=S=O, R 1 =H, R 2 =4-O 2 NC 6 H 4 , R 3 =CH 2 SPh, R 4 =CH 3 ) into a 10 mL reaction tube, add bromine Cuprous chloride (3eq), 2-aminopyridine (3eq), hydrogen peroxide (3eq), and DMF 2mL were added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3-methyl-3-anisthiomethylether-1-4'-nitrobenzenesulfonylindoline was obtained by separation by column chromatography with a yield of 91%.
制备例5Preparation Example 5
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝Bn,R3＝Br,R4＝CH2CH3)，加入碘化亚铜(0.1eq)，氮甲基咪唑(2eq),滴加过氧化氢叔丁基(1eq),滴加乙腈2mL，反应在140℃下进行12h。反应结束后，经柱层析分离得到3-乙基-3溴吲哚啉-1-苄基甲酮，产率为87％。Add amide compound II (X=C, R 1 =H, R 2 =Bn, R 3 =Br, R 4 =CH 2 CH 3 ) into a 10mL reaction tube, add cuprous iodide (0.1eq), nitrogen Methylimidazole (2eq), tert-butyl hydroperoxide (1eq) was added dropwise, acetonitrile 2mL was added dropwise, and the reaction was carried out at 140°C for 12h. After the reaction was completed, 3-ethyl-3-bromoindoline-1-benzyl ketone was obtained by separation by column chromatography with a yield of 87%.
制备例6Preparation Example 6
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝6-4’-C6H5OCH3,R2＝CH(CH3)2,R3＝Ph,R4＝CH2OAc)，加入溴化亚铜(1.5eq)，2-氨基吡啶(3eq),滴加过氧化叔丁基异丙(基)苯(1eq),滴加对氯甲苯2mL，反应在130℃下进行24h。反应结束后，经柱层析分离得到7-4’-甲氧基苯基4-乙酸甲酯基-3-苯基吲哚啉-1-异丙基甲酮，产率为89％。Add amide compound II (X=C, R 1 =6-4'-C 6 H 5 OCH 3 , R 2 =CH(CH 3 ) 2 , R 3 =Ph, R 4 =CH 2 into a 10 mL reaction tube OAc), add cuprous bromide (1.5eq), 2-aminopyridine (3eq), dropwise add tert-butylisopropyl (yl)benzene (1eq), dropwise add p-chlorotoluene 2mL, react at 130°C for 24h . After the reaction was completed, 7-4'-methoxyphenyl 4-acetate methyl group-3-phenylindoline-1-isopropyl ketone was obtained by column chromatography separation with a yield of 89%.
制备例7Preparation Example 7
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝6-C6H6,R2＝CH2CH3,R3＝CH2OCH3,R4＝Cy)，加入溴化亚铜(2eq)，2-吡咯甲酸(2eq),滴加过氧化氢(2eq),滴加DMF 2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3-乙醚基-4环己基-7-苯基吲哚啉-1-丙酮，产率为83％。Add amide compound II (X=C, R 1 =6-C 6 H 6 , R 2 =CH 2 CH 3 , R 3 =CH 2 OCH 3 , R 4 =Cy) into a 10mL reaction tube, add bromide Cuprous (2eq), 2-pyrrolecarboxylic acid (2eq), hydrogen peroxide (2eq), and DMF 2mL were added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3-ethyl ether group-4cyclohexyl-7-phenylindoline-1-propanone was obtained by column chromatography separation with a yield of 83%.
制备例8Preparation example 8
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2,6-di-F-C6H3,R3＝Ph,R4＝CH2SPh)，加入溴化亚铜(1.5eq)，吡啶(3eq),滴加过氧化氢叔丁基(1eq),滴加DMSO 2mL，反应在160℃下进行12h。反应结束后，经柱层析分离得到3-苯基-3-苯甲醚基吲哚啉-1-2’,6’-二氟苯基甲酮，产率为92％。Add amide compound II (X=C, R 1 =H, R 2 =2,6-di-FC 6 H 3 , R 3 =Ph, R 4 =CH 2 SPh) into a 10mL reaction tube, add bromide Cuprous (1.5eq), pyridine (3eq), tert-butyl hydroperoxide (1eq) was added dropwise, DMSO 2mL was added dropwise, and the reaction was carried out at 160°C for 12h. After the reaction was completed, 3-phenyl-3-anisole indoline-1-2',6'-difluorophenyl ketone was obtained by separation by column chromatography with a yield of 92%.
制备例9Preparation Example 9
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2-O2N-C6H4,R3、R4＝CH2OAc)，加入氯化亚铜(2eq)，氮甲基咪唑(2eq),滴加过氧化二叔丁基(3eq),滴加DMF2mL，反应在100℃下进行40h。反应结束后，经柱层析分离得到3,3-二乙酸甲酯基吲哚啉-1-2’-硝基苯基甲酮，产率为84％。Add amide compound II (X=C, R 1 =H, R 2 =2-O 2 NC 6 H 4 , R 3 , R 4 =CH 2 OAc) into a 10 mL reaction tube, add cuprous chloride (2eq ), nitrogen methyl imidazole (2eq), di-tert-butyl peroxide (3eq) was added dropwise, DMF2mL was added dropwise, and the reaction was carried out at 100°C for 40h. After the reaction was completed, 3,3-diacetoxymethylindoline-1-2'-nitrophenyl ketone was obtained by column chromatography separation with a yield of 84%.
制备例10Preparation Example 10
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝4-F-C6H4,R3＝CH2CH3,R4＝Cy)，加入氯化亚铜(0.25eq)，2-吡咯甲酸(3eq),滴加过氧化二叔丁基(1eq),滴加DMSO2mL，反应在160℃下进行12h。反应结束后，经柱层析分离得到3-乙基-3环己基吲哚啉-1-4’-氟苯基甲酮，产率为67％。Add amide compound II (X=C, R 1 =H, R 2 =4-FC 6 H 4 , R 3 =CH 2 CH 3 , R 4 =Cy) into a 10mL reaction tube, add cuprous chloride ( 0.25eq), 2-pyrrolecarboxylic acid (3eq), di-tert-butyl peroxide (1eq) was added dropwise, DMSO2mL was added dropwise, and the reaction was carried out at 160°C for 12h. After the reaction was completed, 3-ethyl-3cyclohexylindoline-1-4'-fluorophenyl ketone was obtained by column chromatography separation with a yield of 67%.
制备例11Preparation Example 11
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝C6H5,R3＝Bn,R4＝CH3)，加入碘化亚铜(3eq)，苯并三氮(2eq),滴加过氧化氢(2eq),滴加对氯甲苯2mL，反应在130℃下进行24h。反应结束后，经柱层析分离得到3-甲基-3-苄基吲哚啉-1-苯基甲酮，产率为92％。Add amide compound II (X=C, R 1 =H, R 2 =C 6 H 5 , R 3 =Bn, R 4 =CH 3 ) into a 10mL reaction tube, add cuprous iodide (3eq), benzene Add triazine (2eq), add hydrogen peroxide (2eq) dropwise, add p-chlorotoluene 2mL dropwise, and carry out the reaction at 130°C for 24h. After the reaction was completed, 3-methyl-3-benzylindoline-1-phenylmethanone was obtained by column chromatography separation with a yield of 92%.
制备例12Preparation Example 12
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2-CH3-C6H4,R3、R4＝CH2SPh)，加入溴化亚铜(2eq)，2-氨基吡啶(3eq),滴加过氧化叔丁基异丙(基)苯(3eq),滴加均氯甲苯2mL，反应在160℃下进行4h。反应结束后，经柱层析分离得到3,3-二苯甲硫醚基吲哚啉-1-2’-甲基苯基甲酮，产率为94％。Add amide compound II (X=C, R 1 =H, R 2 =2-CH 3- C 6 H 4 , R 3 , R 4 =CH 2 SPh) into a 10mL reaction tube, add cuprous bromide ( 2eq), 2-aminopyridine (3eq), tert-butyl cumene peroxide (3eq) was added dropwise, 2mL of m-chlorotoluene was added dropwise, and the reaction was carried out at 160°C for 4h. After the reaction was completed, 3,3-diphenylmethylsulfide indoline-1-2'-methyl phenyl ketone was obtained by column chromatography separation with a yield of 94%.
制备例13Preparation Example 13
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2-F-C6H4,R3＝CH2OCH3,R4＝CH2OAc)，加入溴化亚铜(1.5eq)，三苯基膦(1eq),滴加过氧化氢叔丁基(2eq),滴加对氯甲苯2mL，反应在130℃下进行24h。反应结束后，经柱层析分离得到3-乙醚基-3乙酸乙酯基吲哚啉-1-2’-氟苯基甲酮，产率为82％。Add amide compound II (X=C, R 1 =H, R 2 =2-FC 6 H 4 , R 3 =CH 2 OCH 3 , R 4 =CH 2 OAc) into a 10mL reaction tube, add Copper (1.5eq), triphenylphosphine (1eq), tert-butyl hydroperoxide (2eq) were added dropwise, p-chlorotoluene 2mL was added dropwise, and the reaction was carried out at 130°C for 24h. After the reaction was completed, 3-ethyl ether-3-acetate ethyl indoline-1-2'-fluorophenyl ketone was obtained by separation by column chromatography with a yield of 82%.
制备例14Preparation Example 14
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2,6-di-H3CO-C6H3,R3＝Ph,R4＝Cy)，加入碘化亚铜(0.25eq)，氮甲基咪唑(2eq),滴加过氧化二叔丁基(1eq),滴加DMSO 2mL，反应在160℃下进行12h。反应结束后，经柱层析分离得到3-环己基-3-苯基吲哚啉-1-2’,6’-二甲氧基苯基甲酮，产率为72％。Add amide compound II (X=C, R 1 =H, R 2 =2,6-di-H 3 CO-C 6 H 3 , R 3 =Ph, R 4 =Cy) into a 10mL reaction tube, add Cuprous iodide (0.25eq), nitrogen methyl imidazole (2eq), di-tert-butyl peroxide (1eq) was added dropwise, DMSO 2mL was added dropwise, and the reaction was carried out at 160°C for 12h. After the reaction was completed, 3-cyclohexyl-3-phenylindoline-1-2',6'-dimethoxyphenyl ketone was obtained by column chromatography separation with a yield of 72%.
制备例15Preparation Example 15
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2,4-di-H3C-C6H4,R3＝CH2SPh,R4＝Cy)，加入溴化亚铜(1.5eq)，4-甲基咪唑(2eq),滴加过氧化二叔丁基(3eq),滴加对氯甲苯2mL，反应在130℃下进行24h。反应结束后，经柱层析分离得到3-环己基-3-苯甲硫醚基吲哚啉-1-2’,4’-二甲基苯基甲酮，产率为74％。Add amide compound II (X=C, R 1 =H, R 2 =2,4-di-H 3 CC 6 H 4 , R 3 =CH 2 SPh, R 4 =Cy) into a 10mL reaction tube, add Cuprous bromide (1.5eq), 4-methylimidazole (2eq), di-tert-butyl peroxide (3eq) were added dropwise, p-chlorotoluene 2mL was added dropwise, and the reaction was carried out at 130°C for 24h. After the reaction was completed, 3-cyclohexyl-3-anisolesulfide indoline-1-2',4'-dimethyl phenyl ketone was separated by column chromatography with a yield of 74%.
制备例16Preparation Example 16
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝4-SO3H,R2＝CH3,R3＝CH2CH3,R4＝CH2OAc)，加入溴化亚铜(0.25eq)，三苯基膦(3eq),滴加过氧化氢(1eq),滴加DMF 2mL，反应在100℃下进行40h。反应结束后，经柱层析分离得到3-乙基-3-乙酸甲酯基-5-磺酸基吲哚啉-1-乙酮，产率为23％。Add amide compound II (X=C, R 1 =4-SO 3 H, R 2 =CH 3 , R 3 =CH 2 CH 3 , R 4 =CH 2 OAc) into a 10 mL reaction tube, add oxybromide Copper (0.25eq), triphenylphosphine (3eq), hydrogen peroxide (1eq), and DMF 2mL were added dropwise, and the reaction was carried out at 100°C for 40h. After the reaction was completed, 3-ethyl-3-acetate methyl-5-sulfonate indoline-1-ethanone was obtained by column chromatography separation with a yield of 23%.
制备例17Preparation Example 17
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2-Py,R3＝CH2OCH3,R4＝CH2SPh)，加入氯化亚铜(2eq)，4-甲基咪唑(2eq),滴加过氧化氢叔丁基(2eq),滴加DMF2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3-乙醚基-3-苯甲硫醚基吲哚啉-1-2’-吡啶基甲酮，产率为75％。Add amide compound II (X=C, R 1 =H, R 2 =2-Py, R 3 =CH 2 OCH 3 , R 4 =CH 2 SPh) into a 10mL reaction tube, add cuprous chloride (2eq ), 4-methylimidazole (2eq), tert-butyl hydroperoxide (2eq) was added dropwise, DMF2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3-ethyl ether group-3-anisole sulfide indoline-1-2'-pyridyl ketone was separated by column chromatography with a yield of 75%.
制备例18Preparation Example 18
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2-C4H4S,R3、R4＝Cy)，加入溴化亚铜(3eq)，2-氨基吡啶(2eq),滴加过氧化叔丁基异丙(基)苯(1eq),滴加均氯甲苯2mL，反应在160℃下进行4h。反应结束后，经柱层析分离得到3,3-二环己基吲哚啉-1-2’-噻吩基甲酮，产率为85％。Add amide compound II (X=C, R 1 =H, R 2 =2-C 4 H 4 S, R 3 , R 4 =Cy) into a 10mL reaction tube, add cuprous bromide (3eq), 2 -Aminopyridine (2eq), tert-butylisopropyl (yl)benzene peroxide (1eq) was added dropwise, m-chlorotoluene 2mL was added dropwise, and the reaction was carried out at 160°C for 4h. After the reaction was completed, 3,3-dicyclohexylindoline-1-2'-thienyl ketone was obtained by column chromatography separation with a yield of 85%.
制备例19Preparation Example 19
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝2-F3C-C6H4,R3＝Ph,R4＝CH2OAc)，加入氯化亚铜(1eq)，2-吡咯甲酸(2eq),滴加过氧化氢(0.1eq),滴加对氯甲苯2mL，反应在130℃下进行24h。反应结束后，经柱层析分离得到3-乙酸甲酯基-3-苯基吲哚啉-1-2’-三氟甲基苯基甲酮，产率为77％。Add amide compound II (X=C, R 1 =H, R 2 =2-F 3 CC 6 H 4 , R 3 =Ph, R 4 =CH 2 OAc) into a 10mL reaction tube, add cuprous chloride (1eq), 2-pyrrolecarboxylic acid (2eq), hydrogen peroxide (0.1eq) was added dropwise, p-chlorotoluene 2mL was added dropwise, and the reaction was carried out at 130°C for 24h. After the reaction was completed, 3-acetate methyl-3-phenylindoline-1-2'-trifluoromethyl phenyl ketone was obtained by column chromatography separation with a yield of 77%.
制备例20Preparation Example 20
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝6-CH3,R2＝C6H5,R3＝CH2CH3,R4＝CH2SPh)，加入碘化亚铜(2eq)，2-氨基吡啶(2eq),滴加过氧化二叔丁基(2eq),滴加DMF2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到7-甲基-3-乙基-3-苯甲硫醚基吲哚啉-1-苯基甲酮，产率为95％。Add amide compound II (X=C, R 1 =6-CH 3 , R 2 =C 6 H 5 , R 3 =CH 2 CH 3 , R 4 =CH 2 SPh) into a 10 mL reaction tube, add iodide Cuprous (2eq), 2-aminopyridine (2eq), di-tert-butyl peroxide (2eq) were added dropwise, DMF2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 7-methyl-3-ethyl-3-anisolesulfide indoline-1-phenylmethanone was obtained by column chromatography separation with a yield of 95%.
制备例21Preparation 21
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝6-Cl,R2＝C6H5,R3＝Bn,R4＝Cy)，加入氯化亚铜(2eq)，氮甲基咪唑(1eq),滴加过氧化二叔丁基(2eq),滴加DMF 2mL，反应在100℃下进行12h。反应结束后，经柱层析分离得到3-环己基-3-苄-7-氯吲哚啉-1-苯基甲酮，产率为80％。Add amide compound II (X=C, R 1 =6-Cl, R 2 =C 6 H 5 , R 3 =Bn, R 4 =Cy) into a 10mL reaction tube, add cuprous chloride (2eq), Nitromethylimidazole (1eq), di-tert-butyl peroxide (2eq) was added dropwise, DMF 2mL was added dropwise, and the reaction was carried out at 100°C for 12h. After the reaction was completed, 3-cyclohexyl-3-benzyl-7-chloroindoline-1-phenylmethanone was obtained by separation by column chromatography with a yield of 80%.
制备例22Preparation 22
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝4-Py,R2＝Bn,R3、R4＝CH2SPh)，加入溴化亚铜(1.5eq)，氮甲基咪唑(2eq),滴加过氧化二叔丁基(2eq),滴加对氯甲苯2mL，反应在130℃下进行130h。反应结束后，经柱层析分离得到3,3-二苯甲硫醚基-5-吡啶基吲哚啉-1-苄基甲酮，产率为61％。Add amide compound II (X=C, R 1 =4-Py, R 2 =Bn, R 3 , R 4 =CH 2 SPh) into a 10mL reaction tube, add cuprous bromide (1.5eq), nitrogen form Di-tert-butyl peroxide (2eq) was added dropwise to imidazole (2eq), and p-chlorotoluene 2mL was added dropwise, and the reaction was carried out at 130°C for 130h. After the reaction was completed, 3,3-diphenylmethylsulfide-5-pyridylindoline-1-benzyl ketone was obtained by column chromatography separation with a yield of 61%.
制备例23Preparation Example 23
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝CHCHCH3,R3＝CH2OCH3,R4＝CH2SPh)，加入溴化亚铜(1eq)，2-氨基吡啶(1eq),滴加过氧化氢(1eq),滴加DMF 2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3-乙醚基-3-苯甲硫醚基吲哚啉-1-丙基甲酮，产率为78％。Add amide compound II (X=C, R 1 =H, R 2 =CHCHCH 3 , R 3 =CH 2 OCH 3 , R 4 =CH 2 SPh) into a 10mL reaction tube, add cuprous bromide (1eq) , 2-aminopyridine (1eq), hydrogen peroxide (1eq) was added dropwise, DMF 2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3-ethyl ether group-3-anisole sulfide indoline-1-propyl ketone was obtained by column chromatography separation with a yield of 78%.
制备例24Preparation Example 24
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝C(CH3)3,R3＝Ph,R4＝CH2SPh)，加入溴化亚铜单质(0.25eq)，氮甲基咪唑(2eq),滴加过氧化氢(10eq),滴加DMF2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3-苯基-3-苯甲硫醚基吲哚啉-1-叔丁基甲酮，产率为85％。Add amide compound II (X=C, R 1 =H, R 2 =C(CH 3 ) 3 , R 3 =Ph, R 4 =CH 2 SPh) into a 10mL reaction tube, add cuprous bromide ( 0.25eq), nitrogen methyl imidazole (2eq), hydrogen peroxide (10eq) was added dropwise, DMF2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3-phenyl-3-anisolesulfide indoline-1-tert-butyl ketone was obtained by column chromatography separation with a yield of 85%.
制备例25Preparation 25
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝6-Cy,R2＝C6H5,R3＝Bn,R4＝CH2OAc)，溴化亚铜单质(2eq)，2-吡咯甲酸(1eq),滴加过氧化氢(10eq),滴加DMF 2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3-乙酸甲酯基-7-环己基-3-苄基吲哚啉-1-苯基甲酮，产率为81％。Add amide compound II (X=C, R 1 =6-Cy, R 2 =C 6 H 5 , R 3 =Bn, R 4 =CH 2 OAc), cuprous bromide (2eq ), 2-pyrrolecarboxylic acid (1eq), hydrogen peroxide (10eq) was added dropwise, DMF 2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3-acetate methyl-7-cyclohexyl-3-benzylindoline-1-phenylmethanone was obtained by separation by column chromatography with a yield of 81%.
制备例26Preparation Example 26
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝6-Cy,R2＝C6H5,R3＝Ph,R4＝Cy)，溴化亚铜单质(1eq)，2-氨基吡啶(1eq),滴加过氧化氢(2eq),滴加DMF 2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3,7-二环己基-3-苯基吲哚啉-1-苯基甲酮，产率为89％。Add amide compound II (X=C, R 1 =6-Cy, R 2 =C 6 H 5 , R 3 =Ph, R 4 =Cy), cuprous bromide (1eq) into a 10mL reaction tube, 2-Aminopyridine (1eq), hydrogen peroxide (2eq) was added dropwise, DMF 2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3,7-dicyclohexyl-3-phenylindoline-1-phenylmethanone was obtained by column chromatography separation with a yield of 89%.
制备例27Preparation Example 27
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝H,R2＝CH2CH2Cl,R3＝CH2CH3,R4＝CH2SPh)，溴化亚铜单质(0.25eq)，2-吡咯甲酸(1eq),滴加过氧化氢(0.1eq),滴加DMF 2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3-乙基-3-苯甲硫醚基吲哚啉-1-2’-氯乙基甲酮，产率为84％。Add amide compound II (X=C, R 1 =H, R 2 =CH 2 CH 2 Cl, R 3 =CH 2 CH 3 , R 4 =CH 2 SPh) and cuprous bromide into a 10mL reaction tube (0.25eq), 2-pyrrolecarboxylic acid (1eq), hydrogen peroxide (0.1eq) was added dropwise, DMF 2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3-ethyl-3-anisolesulfide indoline-1-2'-chloroethyl ketone was obtained by column chromatography separation with a yield of 84%.
制备例28Preparation Example 28
在10mL反应管中加入酰胺类化合物II(X＝C,R1＝4-Br,R2＝CH2CH3,R3、R4＝Cy)，溴化亚铜单质(1eq)，氮甲基咪唑(1eq),滴加过氧化氢(1eq),滴加DMF 2mL，反应在100℃下进行24h。反应结束后，经柱层析分离得到3,3-二甲基-5-溴吲哚啉-1-乙基甲酮，产率为92％。In a 10mL reaction tube, add amide compound II (X=C, R 1 =4-Br, R 2 =CH 2 CH 3 , R 3 , R 4 =Cy), cuprous bromide (1eq), nitrogen form imidazole (1eq), hydrogen peroxide (1eq) was added dropwise, DMF 2mL was added dropwise, and the reaction was carried out at 100°C for 24h. After the reaction was completed, 3,3-dimethyl-5-bromoindoline-1-ethyl ketone was obtained by column chromatography separation with a yield of 92%.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The above-mentioned embodiments only express several implementation modes of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.
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